HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Herceptin safely and effectively. See full prescribing information for Herceptin.
HERCEPTIN® (trastuzumab) for injection, for intravenous use Initial U.S. Approval: 1998
WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY See full prescribing information for complete boxed warning
Cardiomyopathy: Herceptin can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracyclines. Evaluate cardiac function prior to and during treatment. Discontinue Herceptin for cardiomyopathy. (2.3, 5.1)
Infusion Reactions, Pulmonary Toxicity: Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. (5.2, 5.4)
Embryo-Fetal Toxicity: Exposure to Herceptin during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death. Advise patients of these risks and the need for effective contraception. (5.3, 8.1, 8.3)
---INDICATIONS AND USAGE--- Herceptin is a HER2/neu receptor antagonist indicated for:
• The treatment of HER2-overexpressing breast cancer. (1.1, 1.2)
• The treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. (1.3)
Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin (1, 2.1).
---DOSAGE AND ADMINISTRATION---
For intravenous (IV) infusion only. Do not administer as an IV push or bolus. (2.2)
Do not substitute Herceptin (trastuzumab) for or with ado-trastuzumab emtansine. (2.2)
Perform HER2 testing using FDA-approved tests by laboratories with demonstrated proficiency. (1, 2.1)
Adjuvant Treatment of HER2-Overexpressing Breast Cancer (2.2) Administer at either:
• Initial dose of 4 mg/kg over 90 minute IV infusion, then 2 mg/kg over 30 minute IV infusion weekly for 12 weeks (with paclitaxel or docetaxel) or 18 weeks (with docetaxel/carboplatin). One week after the last weekly dose of Herceptin, administer 6 mg/kg as an IV infusion over 30−90 minutes every three weeks to complete a total of 52 weeks of therapy, or
• Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over 30−90 minutes IV infusion every three weeks for 52 weeks.
Metastatic HER2-Overexpressing Breast Cancer (2.2)
• Initial dose of 4 mg/kg as a 90 minute IV infusion followed by subsequent weekly doses of 2 mg/kg as 30 minute IV infusions.
Metastatic HER2-Overexpressing Gastric Cancer (2.2)
• Initial dose of 8 mg/kg over 90 minutes IV infusion, followed by 6 mg/kg over 30 to 90 minutes IV infusion every 3 weeks.
---DOSAGE FORMS AND STRENGTHS---
• For Injection: 150 mg lyophilized powder in a single-dose vial for reconstitution
• For Injection: 420 mg lyophilized powder in a multiple-dose vial for reconstitution
---CONTRAINDICATIONS---
• None. (4)
---WARNINGS AND PRECAUTIONS---
• Exacerbation of Chemotherapy-Induced Neutropenia. (5.5, 6.1) ---ADVERSE REACTIONS--- Adjuvant Breast Cancer
• Most common adverse reactions (≥ 5%) are headache, diarrhea, nausea, and chills. (6.1)
Metastatic Breast Cancer
• Most common adverse reactions (≥ 10%) are fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash. (6.1) Metastatic Gastric Cancer
• Most common adverse reactions (≥ 10%) are neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia.
(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
---USE IN SPECIFIC POPULATIONS---
Females and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of Herceptin (8.3).
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 11/2018 FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING − CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY 1 INDICATIONS AND USAGE
1.1 Adjuvant Breast Cancer 1.2 Metastatic Breast Cancer 1.3 Metastatic Gastric Cancer 2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
2.2 Recommended Doses and Schedules 2.3 Important Dosing Considerations 2.4 Preparation for Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS 5.1 Cardiomyopathy
5.2 Infusion Reactions 5.3 Embryo-Fetal Toxicity 5.4 Pulmonary Toxicity
5.5 Exacerbation of Chemotherapy-Induced Neutropenia 6 ADVERSE REACTIONS
6.1 Clinical Trials Experience 6.2 Immunogenicity
6.3 Post-Marketing Experience 7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES
14.1 Adjuvant Breast Cancer 14.2 Metastatic Breast Cancer 14.3 Metastatic Gastric Cancer
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied
16.2 Stability and Storage
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY
Cardiomyopathy
Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with
anthracycline-containing chemotherapy regimens.
Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. Discontinue Herceptin treatment in patients receiving adjuvant therapy and withhold Herceptin in patients with metastatic disease for clinically significant decrease in left ventricular function [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
Infusion Reactions; Pulmonary Toxicity
Herceptin administration can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of Herceptin administration.
Interrupt Herceptin infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue Herceptin for anaphylaxis,
angioedema, interstitial pneumonitis, or acute respiratory distress syndrome [see Warnings and Precautions (5.2, 5.4)].
Embryo-Fetal Toxicity
Exposure to Herceptin during pregnancy can result in oligohydramnios and
oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)].
1 INDICATIONS AND USAGE 1.1 Adjuvant Breast Cancer
Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies (14.1)]) breast cancer
• as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
• as part of a treatment regimen with docetaxel and carboplatin
• as a single agent following multi-modality anthracycline based therapy.
Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see Dosage and Administration (2.1)].
1.2 Metastatic Breast Cancer Herceptin is indicated:
• In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
• As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.
Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see Dosage and Administration (2.1)].
1.3 Metastatic Gastric Cancer
Herceptin is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction
Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see Dosage and Administration (2.1)].
2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection
Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast or gastric cancers by laboratories with demonstrated proficiency. Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene
amplification is available at: http://www.fda.gov/CompanionDiagnostics.
Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.
Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.
2.2 Recommended Doses and Schedules
• Do not administer as an intravenous push or bolus. Do not mix Herceptin with other drugs.
• Do not substitute Herceptin (trastuzumab) for or with ado-trastuzumab emtansine.
Adjuvant Treatment, Breast Cancer
Administer according to one of the following doses and schedules for a total of 52 weeks of Herceptin therapy:
During and following paclitaxel, docetaxel, or docetaxel/carboplatin:
• Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin).
• One week following the last weekly dose of Herceptin, administer Herceptin at 6 mg/kg as an intravenous infusion over 30−90 minutes every three weeks.
As a single agent within three weeks following completion of multi-modality, anthracycline-based chemotherapy regimens:
• Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes
• Subsequent doses at 6 mg/kg as an intravenous infusion over 30−90 minutes every three weeks [see Dosage and Administration (2.3)].
• Extending adjuvant treatment beyond one year is not recommended [see Adverse Reactions (6.1)].
Metastatic Treatment, Breast Cancer
• Administer Herceptin, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as a 90-minute intravenous infusion followed by subsequent once weekly doses of 2 mg/kg as 30-minute intravenous infusions until disease progression.
Metastatic Gastric Cancer
• Administer Herceptin at an initial dose of 8 mg/kg as a 90-minute intravenous infusion
followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks until disease progression [see Dosage and Administration (2.3)].
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2.3 Important Dosing Considerations
If the patient has missed a dose of Herceptin by one week or less, then the usual maintenance dose (weekly schedule: 2 mg/kg; three-weekly schedule: 6 mg/kg) should be administered as soon as possible. Do not wait until the next planned cycle. Subsequent Herceptin maintenance doses should be administered 7 days or 21 days later according to the weekly or three-weekly schedules,
respectively.
If the patient has missed a dose of Herceptin by more than one week, a re-loading dose of
Herceptin should be administered over approximately 90 minutes (weekly schedule: 4 mg/kg; three- weekly schedule: 8 mg/kg) as soon as possible. Subsequent Herceptin maintenance doses (weekly schedule: 2 mg/kg; three-weekly schedule 6 mg/kg) should be administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.
Infusion Reactions
[See Boxed Warning, Warnings and Precautions (5.2)]
• Decrease the rate of infusion for mild or moderate infusion reactions
• Interrupt the infusion in patients with dyspnea or clinically significant hypotension
• Discontinue Herceptin for severe or life-threatening infusion reactions.
Cardiomyopathy
[See Boxed Warning, Warnings and Precautions (5.1)]
Assess left ventricular ejection fraction (LVEF) prior to initiation of Herceptin and at regular intervals during treatment. Withhold Herceptin dosing for at least 4 weeks for either of the following:
• ≥ 16% absolute decrease in LVEF from pre-treatment values
• LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values.
Herceptin may be resumed if, within 4−8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%.
Permanently discontinue Herceptin for a persistent (> 8 weeks) LVEF decline or for suspension of Herceptin dosing on more than 3 occasions for cardiomyopathy.
2.4 Preparation for Administration
To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is Herceptin (trastuzumab) and not ado-trastuzumab emtansine.
420 mg Multiple-dose vial Reconstitution
Reconstitute each 420 mg vial of Herceptin with 20 mL of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative to yield a multiple-dose solution containing 21 mg/mL trastuzumab that delivers 20 mL (420 mg trastuzumab). In patients with known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection (SWFI) without preservative to yield a single use solution.
Use appropriate aseptic technique when performing the following reconstitution steps:
• Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the lyophilized powder of Herceptin, which has a cake-like appearance. The stream of diluent should be directed into the cake. The reconstituted vial yields a solution for multiple-dose use, containing 21 mg/mL trastuzumab.
• Swirl the vial gently to aid reconstitution. DO NOT SHAKE.
• Slight foaming of the product may be present upon reconstitution. Allow the vial to stand
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for
particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow.
• Store reconstituted Herceptin in the refrigerator at 2○C to 8○C (36°F to 46°F); discard unused Herceptin after 28 days. If Herceptin is reconstituted with SWFI without preservative, use immediately and discard any unused portion. Do not freeze.
Dilution
• Determine the dose (mg) of Herceptin [see Dosage and Administration (2.2)]. Calculate the volume of the 21 mg/mL reconstituted Herceptin solution needed, withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION.
• Gently invert the bag to mix the solution.
• The solution of Herceptin for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours prior to use. Do not freeze.
150 mg Single-dose vial Reconstitution
Reconstitute each 150 mg vial of Herceptin with 7.4 mL of Sterile Water for Injection (SWFI) (not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab that delivers 7.15 mL (150 mg trastuzumab).
Use appropriate aseptic technique when performing the following reconstitution steps:
• Using a sterile syringe, slowly inject 7.4 mL of SWFI (not supplied) into the vial containing the lyophilized powder of Herceptin, which has a cake-like appearance. The stream of diluent should be directed into the cake. The reconstituted vial yields a solution for single-dose use, containing 21 mg/mL trastuzumab.
• Swirl the vial gently to aid reconstitution. DO NOT SHAKE.
• Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for
particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow.
• Use the Herceptin solution immediately following reconstitution with SWFI, as it contains no preservative and is intended for single-dose only. If not used immediately, store the
reconstituted Herceptin solution for up to 24 hours at 2○C to 8○C (36○F to 46○F); discard any unused Herceptin after 24 hours. Do not freeze.
Dilution
• Determine the dose (mg) of Herceptin [see Dosage and Administration (2.1)].
• Calculate the volume of the 21 mg/mL reconstituted Herceptin solution needed.
• Withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION.
• Gently invert the bag to mix the solution.
• The solution of Herceptin for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours prior to use. Discard after 24 hours. This storage time is additional to the time allowed for the reconstituted vials. Do not freeze.
5
3 DOSAGE FORMS AND STRENGTHS
• For injection: 150 mg lyophilized powder in a single-dose vial
• For injection: 420 mg lyophilized powder in a multiple-dose vial.
4 CONTRAINDICATIONS None.
5 WARNINGS AND PRECAUTIONS 5.1 Cardiomyopathy
Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy].
Herceptin can also cause asymptomatic decline in left ventricular ejection fraction (LVEF).
There is a 4−6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving Herceptin as a single agent or in combination therapy compared with those not receiving Herceptin. The highest absolute incidence occurs when Herceptin is administered with an anthracycline.
Withhold Herceptin for ≥ 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values [see Dosage and Administration (2.3)]. The safety of continuation or resumption of
Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied.
Patients who receive anthracycline after stopping Herceptin may also be at increased risk of cardiac dysfunction [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
Cardiac Monitoring
Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:
• Baseline LVEF measurement immediately prior to initiation of Herceptin
• LVEF measurements every 3 months during and upon completion of Herceptin
• Repeat LVEF measurement at 4 week intervals if Herceptin is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration (2.3)]
• LVEF measurements every 6 months for at least 2 years following completion of Herceptin as a component of adjuvant therapy.
In Study 1, 15% (158/1031) of patients discontinued Herceptin due to clinical evidence of myocardial dysfunction or significant decline in LVEF after a median follow-up duration of
8.7 years in the AC-TH arm. In Study 3 (one-year Herceptin treatment), the number of patients who discontinued Herceptin due to cardiac toxicity at 12.6 months median duration of follow-up was 2.6% (44/1678). In Study 4, a total of 2.9% (31/1056) of patients in the TCH arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) of patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase)
discontinued Herceptin due to cardiac toxicity.
Among 64 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive heart failure, one patient died of cardiomyopathy, one patient died suddenly without documented etiology, and 33 patients were receiving cardiac medication at last follow-up. Approximately 24%
of the surviving patients had recovery to a normal LVEF (defined as ≥ 50%) and no symptoms on continuing medical management at the time of last follow-up. Incidence of congestive heart failure
Table 1
Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies
Incidence of CHF
Study Regimen Herceptin Control
1 & 2a ACb→Paclitaxel+Herceptin 3.2% (64/2000)c 1.3% (21/1655)
3d Chemo→ Herceptin 2% (30/1678) 0.3% (5/1708)
4 ACb→Docetaxel+Herceptin 2% (20/1068) 0.3% (3/1050)
4 Docetaxel+Carbo+Herceptin 0.4% (4/1056) 0.3% (3/1050)
a Median follow-up duration for studies 1 and 2 combined was 8.3 years in the AC→TH arm.
b Anthracycline (doxorubicin) and cyclophosphamide.
c Includes 1 patient with fatal cardiomyopathy and 1 patient with sudden death without documented etiology.
d Includes NYHA II-IV and cardiac death at 12.6 months median duration of follow-up in the one-year Herceptin arm.
In Study 3 (one-year Herceptin treatment), at a median follow-up duration of 8 years, the incidence of severe CHF (NYHA III & IV) was 0.8%, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%.
Table 2
Incidence of Cardiac Dysfunctiona in Metastatic Breast Cancer Studies
Incidence
NYHA I−IV NYHA III−IV
Study Event Herceptin Control Herceptin Control
5 Cardiac Dysfunction 28% 7% 19% 3%
(AC)b
5 Cardiac Dysfunction 11% 1% 4% 1%
(paclitaxel)
6 Cardiac Dysfunctionc 7% N/A 5% N/A
a Congestive heart failure or significant asymptomatic decrease in LVEF.
b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
c Includes 1 patient with fatal cardiomyopathy.
In Study 4, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in the Herceptin containing regimens (AC-TH: 0.3% (3/1068) and TCH: 0.2% (2/1056)) as compared to none in AC-T.
5.2 Infusion Reactions
Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia [see Adverse Reactions (6.1)].
In post-marketing reports, serious and fatal infusion reactions have been reported. Severe
reactions, which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable, including progressive worsening, initial improvement followed by
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clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction.
Interrupt Herceptin infusion in all patients experiencing dyspnea, clinically significant
hypotension, and intervention of medical therapy administered (which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen). Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions.
There are no data regarding the most appropriate method of identification of patients who may safely be retreated with Herceptin after experiencing a severe infusion reaction. Prior to resumption of Herceptin infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated Herceptin infusions, others had recurrent severe infusion reactions despite pre-medications.
5.3 Embryo-Fetal Toxicity
Herceptin can cause fetal harm when administered to a pregnant woman. In post-marketing reports, use of Herceptin during pregnancy resulted in cases of oligohydramnios and
oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.
Verify the pregnancy status of females of reproductive potential prior to the initiation of Herceptin. Advise pregnant women and females of reproductive potential that exposure to
Herceptin during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of Herceptin [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.3)].
5.4 Pulmonary Toxicity
Herceptin use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic
pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions [see Warnings and Precautions (5.2)]. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity.
5.5 Exacerbation of Chemotherapy-Induced Neutropenia
In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3−4 neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received Herceptin and those who did not [see Adverse Reactions (6.1)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the label:
• Cardiomyopathy [see Warnings and Precautions (5.1)]
• Infusion Reactions [see Warnings and Precautions (5.2)]
• Embryo-Fetal Toxicity [see Warnings and Precautions (5.3)]
• Pulmonary Toxicity [see Warnings and Precautions (5.4)]
• Exacerbation of Chemotherapy-Induced Neutropenia [see Warnings and Precautions (5.5)]
The most common adverse reactions in patients receiving Herceptin in the adjuvant and metastatic
requiring interruption or discontinuation of Herceptin treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and Administration (2.3)].
In the metastatic gastric cancer setting, the most common adverse reactions (≥10%) that were increased (≥ 5% difference) in the Herceptin arm as compared to the chemotherapy alone arm were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in discontinuation of treatment on the Herceptin
containing arm in the absence of disease progression were infection, diarrhea, and febrile neutropenia.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adjuvant Breast Cancer Studies
The data below reflect exposure to one-year Herceptin therapy across three randomized, open-label studies, Studies 1, 2, and 3, with (n = 3678) or without (n = 3363) trastuzumab in the adjuvant treatment of breast cancer.
The data summarized in Table 3 below, from Study 3, reflect exposure to Herceptin in
1678 patients; the median treatment duration was 51 weeks and median number of infusions was 18.
Among the 3386 patients enrolled in the observation and one-year Herceptin arms of Study 3 at a median duration of follow-up of 12.6 months in the Herceptin arm, the median age was 49 years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian.
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Table 3
Adverse Reactions for Study 3a, All Gradesb
Adverse Reaction
One Year Herceptin (n = 1678)
Observation (n = 1708) Cardiac
Hypertension 64 (4%)
Dizziness 60 (4%)
Ejection Fraction Decreased 58 (3.5%)
Palpitations 48 (3%)
Cardiac Arrhythmiasc 40 (3%)
Cardiac Failure Congestive 30 (2%)
Cardiac Failure 9 (0.5%)
Cardiac Disorder 5 (0.3%)
Ventricular Dysfunction 4 (0.2%) Respiratory Thoracic Mediastinal Disorders
Cough 81 (5%)
Influenza 70 (4%)
Dyspnea 57 (3%)
URI 46 (3%)
Rhinitis 36 (2%)
Pharyngolaryngeal Pain 32 (2%)
Sinusitis 26 (2%)
Epistaxis 25 (2%)
Pulmonary Hypertension 4 (0.2%) Interstitial Pneumonitis 4 (0.2%) Gastrointestinal Disorders
Diarrhea 123 (7%)
Nausea 108 (6%)
Vomiting 58 (3.5%)
Constipation 33 (2%)
Dyspepsia 30 (2%)
Upper Abdominal Pain 29 (2%)
Musculoskeletal & Connective Tissue Disorders
Arthralgia 137 (8%)
Back Pain 91 (5%)
Myalgia 63 (4%)
Bone Pain 49 (3%)
Muscle Spasm 46 (3%)
Nervous System Disorders
Headache 162 (10%)
Paraesthesia 29 (2%)
Skin & Subcutaneous Tissue Disorders
Rash 70 (4%)
Nail Disorders 43 (2%)
Pruritus 40 (2%)
35 (2%) 29 (2%) 11 (0.6%) 12 (0.7%) 17 (1%) 5 (0.3%) 4 (0.2%) 0 (0%) 0 (0%) 34 (2%) 9 (0.5%) 26 (2%) 20 (1%) 6 (0.4%) 8 (0.5%) 5 (0.3%) 1 (0.06%)
0 (0%) 0 (0%) 16 (1%) 19 (1%) 10 (0.6%)
17 (1%) 9 (0.5%) 15 (1%) 98 (6%) 58 (3%) 17 (1%) 26 (2%) 3 (0.2%) 49 (3%) 11 (0.6%) 10 (0.6%) 0 (0%) 10 (0.6%)
Table 3 (cont’d)
Adverse Reactions for Study 3a, All Gradesb
Adverse Reaction
One Year Herceptin (n = 1678)
Observation (n = 1708) General Disorders
Pyrexia
Edema Peripheral Chills
Asthenia
Influenza-like Illness Sudden Death Infections Nasopharyngitis UTI
Immune System Disorders Hypersensitivity
Autoimmune Thyroiditis
100 (6%) 79 (5%) 85 (5%) 75 (4.5%)
40 (2%) 1 (0.06%)
135 (8%) 39 (3%) 10 (0.6%)
4 (0.3%)
6 (0.4%) 37 (2%) 0 (0%) 30 (2%) 3 (0.2%) 0 (0%) 43 (3%) 13 (0.8%) 1 (0.06%) 0 (0%)
a Median follow-up duration of 12.6 months in the one-year Herceptin treatment arm.
b The incidence of Grade 3 or higher adverse reactions was <1% in both arms for each listed term.
c Higher level grouping term.
In Study 3, a comparison of 3-weekly Herceptin treatment for two years versus one year was also performed. The rate of asymptomatic cardiac dysfunction was increased in the 2-year Herceptin treatment arm (8.1% versus 4.6% in the one-year Herceptin treatment arm). More patients
experienced at least one adverse reaction of Grade 3 or higher in the 2-year Herceptin treatment arm (20.4%) compared with the one-year Herceptin treatment arm (16.3%).
The safety data from Studies 1 and 2 were obtained from 3655 patients, of whom 2000 received Herceptin; the median treatment duration was 51 weeks. The median age was 49 years (range:
24−80); 84% of patients were White, 7% Black, 4% Hispanic, and 3% Asian.
In Study 1, only Grade 3−5 adverse events, treatment-related Grade 2 events, and Grade 2−5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2−5 occurred at an incidence of at least 2% greater among patients receiving Herceptin plus chemotherapy as compared to chemotherapy alone: fatigue (29.5% vs. 22.4%), infection (24.0% vs. 12.8%), hot flashes (17.1% vs. 15.0%), anemia (12.3% vs.
6.7%), dyspnea (11.8% vs. 4.6%), rash/desquamation (10.9% vs. 7.6%), leukopenia (10.5% vs.
8.4%), neutropenia (6.4% vs. 4.3%), headache (6.2% vs. 3.8%), pain (5.5% vs. 3.0%), edema (4.7%
vs. 2.7%), and insomnia (4.3% vs. 1.5%). The majority of these events were Grade 2 in severity.
In Study 2, data collection was limited to the following investigator-attributed treatment-related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3−5 non-hematologic toxicities, selected Grade 2−5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, and sensory neuropathy) and Grade 1−5 cardiac toxicities occurring during chemotherapy and/or Herceptin treatment. The following non-cardiac adverse reactions of
Grade 2−5 occurred at an incidence of at least 2% greater among patients receiving Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (12.2% vs. 9.1%), nail changes (11.5% vs. 6.8%), dyspnea (2.4% vs. 0.2%), and diarrhea (2.2% vs. 0%). The majority of these events were Grade 2 in severity.
Safety data from Study 4 reflect exposure to Herceptin as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n= 1056].
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The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms.
The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and every three week dosing in the monotherapy period. Among these patients, the median age was 49 years (range 22 to 74 years). In Study 4, the toxicity profile was similar to that reported in Studies 1, 2, and 3 with the exception of a low incidence of CHF in the TCH arm.
Metastatic Breast Cancer Studies
The data below reflect exposure to Herceptin in one randomized, open-label study, Study 5, of chemotherapy with (n = 235) or without (n = 234) trastuzumab in patients with metastatic breast cancer, and one single-arm study (Study 6; n = 222) in patients with metastatic breast cancer. Data in Table 4 are based on Studies 5 and 6.
Among the 464 patients treated in Study 5, the median age was 52 years (range: 25−77 years).
Eighty-nine percent were White, 5% Black, 1% Asian, and 5% other racial/ethnic groups.
All patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The
percentages of patients who received Herceptin treatment for ≥ 6 months and ≥ 12 months were 58%
and 9%, respectively.
Among the 352 patients treated in single agent studies (213 patients from Study 6), the median age was 50 years (range 28−86 years), 86% were White, 3% were Black, 3% were Asian, and 8% in other racial/ethnic groups. Most of the patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for ≥ 6 months and ≥ 12 months were 31% and 16%, respectively.
Table 4
Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients in Uncontrolled Studies or at Increased Incidence in the Herceptin Arm (Studies 5 and 6)
Single Agenta n = 352
Herceptin + Paclitaxel
n = 91
Paclitaxel Alone n = 95
Herceptin + ACb n = 143
ACb Alone n = 135 Body as a Whole
Pain 47% 61% 62% 57% 42%
Asthenia 42% 62% 57% 54% 55%
Fever 36% 49% 23% 56% 34%
Chills 32% 41% 4% 35% 11%
Headache 26% 36% 28% 44% 31%
Abdominal pain 22% 34% 22% 23% 18%
Back pain 22% 34% 30% 27% 15%
Infection 20% 47% 27% 47% 31%
Flu syndrome 10% 12% 5% 12% 6%
Accidental injury 6% 13% 3% 9% 4%
Allergic reaction 3% 8% 2% 4% 2%
Cardiovascular
Tachycardia 5% 12% 4% 10% 5%
Congestive heart failure 7% 11% 1% 28% 7%
Table 4 (cont’d)
Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients in Uncontrolled Studies or at Increased Incidence in the Herceptin Arm (Studies 5 and 6)
Single Agenta n = 352
Herceptin + Paclitaxel
n = 91
Paclitaxel Alone n = 95
Herceptin + ACb n = 143
ACb Alone n = 135 Digestive
Nausea 33% 51% 9% 76% 77%
Diarrhea 25% 45% 29% 45% 26%
Vomiting 23% 37% 28% 53% 49%
Nausea and vomiting 8% 14% 11% 18% 9%
Anorexia 14% 24% 16% 31% 26%
Heme & Lymphatic
Anemia 4% 14% 9% 36% 26%
Leukopenia 3% 24% 17% 52% 34%
Metabolic
Peripheral edema 10% 22% 20% 20% 17%
Edema 8% 10% 8% 11% 5%
Musculoskeletal
Bone pain 7% 24% 18% 7% 7%
Arthralgia 6% 37% 21% 8% 9%
Nervous
Insomnia 14% 25% 13% 29% 15%
Dizziness 13% 22% 24% 24% 18%
Paresthesia 9% 48% 39% 17% 11%
Depression 6% 12% 13% 20% 12%
Peripheral neuritis 2% 23% 16% 2% 2%
Neuropathy 1% 13% 5% 4% 4%
Respiratory
Cough increased 26% 41% 22% 43% 29%
Dyspnea 22% 27% 26% 42% 25%
Rhinitis 14% 22% 5% 22% 16%
Pharyngitis 12% 22% 14% 30% 18%
Sinusitis 9% 21% 7% 13% 6%
Skin
Rash 18% 38% 18% 27% 17%
Herpes simplex 2% 12% 3% 7% 9%
Acne 2% 11% 3% 3% < 1%
Urogenital
Urinary tract infection 5% 18% 14% 13% 7%
a Data for Herceptin single agent were from 4 studies, including 213 patients from Study 6.
b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
Metastatic Gastric Cancer
The data below are based on the exposure of 294 patients to Herceptin in combination with a fluoropyrimidine (capecitabine or 5-FU) and cisplatin (Study 7). In the Herceptin plus
chemotherapy arm, the initial dose of Herceptin 8 mg/kg was administered on Day 1 (prior to
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chemotherapy) followed by 6 mg/kg every 21 days until disease progression. Cisplatin was administered at 80 mg/m2 on Day 1 and the fluoropyrimidine was administered as either
capecitabine 1000 mg/m2 orally twice a day on Days 1–14 or 5-fluorouracil 800 mg/m2/day as a continuous intravenous infusion Days 1 through 5. Chemotherapy was administered for six 21-day cycles. Median duration of Herceptin treatment was 21 weeks; median number of Herceptin infusions administered was eight.
Table 5
Study 7: Per Patient Incidence of Adverse Reactions of All Grades (Incidence ≥ 5% between Arms) or Grade 3/4 (Incidence > 1% between Arms)
and Higher Incidence in Herceptin Arm
Herceptin + FC (N = 294)
N (%)
FC (N = 290)
N (%)
Body System/Adverse Event All Grades Grades 3/4 All Grades Grades 3/4 Investigations
Neutropenia 230 (78) 101 (34) 212 (73) 83 (29)
Hypokalemia 83 (28) 28 (10) 69 (24) 16 (6)
Anemia 81 (28) 36 (12) 61 (21) 30 (10)
Thrombocytopenia
Blood and Lymphatic System Disorders Febrile Neutropenia
47 (16)
14 (5) 15 (5)
33 (11)
8 (3) 8 (3) Gastrointestinal Disorders
Diarrhea 109 (37) 27 (9) 80 (28) 11 (4)
Stomatitis 72 (24) 2 (1) 43 (15) 6 (2)
Dysphagia 19 (6) 7 (2) 10 (3) 1 (≤ 1)
Body as a Whole
Fatigue 102 (35) 12 (4) 82 (28) 7 (2)
Fever 54 (18) 3 (1) 36 (12) 0 (0)
Mucosal Inflammation 37 (13) 6 (2) 18 (6) 2 (1)
Chills 23 (8) 1 (≤ 1) 0 (0) 0 (0)
Metabolism and Nutrition Disorders
Weight Decrease 69 (23) 6 (2) 40 (14) 7 (2)
Infections and Infestations
Upper Respiratory Tract Infections 56 (19) 0 (0) 29 (10) 0 (0)
Nasopharyngitis 37 (13) 0 (0) 17 (6) 0 (0)
Renal and Urinary Disorders
Renal Failure and Impairment 53 (18) 8 (3) 42 (15) 5 (2)
Nervous System Disorders
Dysgeusia 28 (10) 0 (0) 14 (5) 0 (0)
The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast cancer, metastatic breast cancer, metastatic gastric cancer, or post-marketing experience.
Cardiomyopathy
Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In Study 3, the median duration of follow-up was 12.6 months
(12.4 months in the observation arm; 12.6 months in the 1-year Herceptin arm); and in Studies 1 and 2, 7.9 years in the AC-T arm, 8.3 years in the AC-TH arm. In Studies 1 and 2, 6% of all randomized patients with post-AC LVEF evaluation were not permitted to initiate Herceptin following
completion of AC chemotherapy due to cardiac dysfunction (LVEF < LLN or ≥ 16 point decline in LVEF from baseline to end of AC). Following initiation of Herceptin therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving Herceptin and paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patients
receiving one-year Herceptin monotherapy compared to observation in Study 3 (see Table 6, Figures 1 and 2). The per-patient incidence of new-onset cardiac dysfunction, as measured by LVEF, remained similar when compared to the analysis performed at a median follow-up of 2.0 years in the AC-TH arm. This analysis also showed evidence of reversibility of left ventricular dysfunction, with 64.5% of patients who experienced symptomatic CHF in the AC-TH group being asymptomatic at latest follow-up, and 90.3% having full or partial LVEF recovery.
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Table 6a
Per-patient Incidence of New Onset
Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4
LVEF < 50%
and Absolute Decrease from Baseline Absolute LVEF Decrease LVEF
< 50%
≥ 10%
decrease
≥ 16%
decrease < 20% and ≥ 10% ≥ 20%
Studies 1 & 2b,c AC→TH (n = 1856)
AC→T (n = 1170) Study 3d
Herceptin (n = 1678) Observation
(n = 1708) Study 4e
TCH (n = 1056)
AC→TH (n = 1068)
AC→T (n = 1050)
23.1%
(428)
18.5%
(344)
11.2%
(208) 11.7%
(137)
7.0%
(82)
3.0%
(35)
8.6%
(144)
7.0%
(118)
3.8%
(64) 2.7%
(46)
2.0%
(35)
1.2%
(20)
8.5%
(90)
5.9%
(62)
3.3%
(35) 17%
(182)
13.3%
(142)
9.8%
(105) 9.5%
(100)
6.6%
(69)
3.3%
(35)
37.9%
(703)
8.9%
(166) 22.1%
(259)
3.4%
(40)
22.4%
(376)
3.5%
(59) 11.9%
(204)
1.2%
(21)
34.5%
(364)
6.3%
(67) 44.3%
(473)
13.2%
(141) 34%
(357)
5.5%
(58)
a For Studies 1, 2 and 3, events are counted from the beginning of Herceptin treatment. For Study 4, events are counted from the date of randomization.
b Studies 1 and 2 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or paclitaxel plus Herceptin (AC→TH).
c Median duration of follow-up for Studies 1 and 2 combined was 8.3 years in the AC→TH arm.
d Median follow-up duration of 12.6 months in the one-year Herceptin treatment arm.
e Study 4 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or docetaxel plus Herceptin (AC→TH); docetaxel and carboplatin plus Herceptin (TCH).
Figure 1
Studies 1 and 2: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to
Below 50% with Death as a Competing Risk Event
Time 0 is initiation of paclitaxel or Herceptin + paclitaxel therapy.
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Figure 2
Study 3: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to
Below 50% with Death as a Competing Risk Event
Time 0 is the date of randomization.
Figure 3
Study 4: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to
Below 50% with Death as a Competing Risk Event
Time 0 is the date of randomization.
The incidence of treatment emergent congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I−IV, where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast cancer trials, the probability of cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracyclines.
In Study 7, 5.0% of patients in the Herceptin plus chemotherapy arm compared to 1.1% of
patients in the chemotherapy alone arm had LVEF value below 50% with a ≥10% absolute decrease in LVEF from pretreatment values.
Infusion Reactions
During the first infusion with Herceptin, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of
Herceptin infusion); permanent discontinuation of Herceptin for infusion reactions was required in
< 1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusion reactions occurred in 21% and 35% of patients, and were severe in 1.4% and 9%
of patients, on second or subsequent Herceptin infusions administered as monotherapy or in combination with chemotherapy, respectively. In the post-marketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported.
Anemia
In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [Study 5]), of selected NCI-CTC Grade 2–5 anemia (12.3% vs. 6.7% [Study 1]), and of anemia requiring transfusions (0.1% vs. 0 patients [Study 2]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. Following the administration of Herceptin as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was < 1%. In Study 7 (metastatic gastric cancer), on the Herceptin containing arm as compared to the
chemotherapy alone arm, the overall incidence of anemia was 28% compared to 21% and of NCI
CTC Grade 3/4 anemia was 12.2% compared to 10.3%.
Neutropenia
In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4−5 neutropenia (1.7% vs. 0.8% [Study 2]) and of selected Grade 2−5 neutropenia (6.4% vs. 4.3% [Study 1]) were increased in patients receiving Herceptin and chemotherapy
compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. In Study 7 (metastatic gastric cancer) on the Herceptin containing arm as compared to the chemotherapy alone arm, the incidence of NCI-CTC Grade 3/4 neutropenia was 36.8% compared to 28.9%; febrile neutropenia 5.1% compared to 2.8%.
Infection
The overall incidences of infection (46% vs. 30% [Study 5]), of selected NCI-CTC Grade 2−5 infection/febrile neutropenia (24.3% vs. 13.4% [Study 1]) and of selected Grade 3−5
infection/febrile neutropenia (2.9% vs. 1.4% [Study 2]) were higher in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract.
In Study 4, the overall incidence of infection was higher with the addition of Herceptin to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of NCI-CTC Grade 3−4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms.
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In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone.
Pulmonary Toxicity Adjuvant Breast Cancer
Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCI-CTC Grade 2−5 pulmonary toxicity (14.3% vs. 5.4% [Study 1]) and of selected NCI-CTC Grade 3−5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 0.9% [Study 2]) was higher in patients receiving Herceptin and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2−5: 11.8% vs. 4.6% [Study 1];
NCI-CTC Grade 2−5: 2.4% vs. 0.2% [Study 2]).
Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving Herceptin compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving Herceptin, one as a component of multi-organ system failure, as compared to 1 patient receiving chemotherapy alone.
In Study 3, there were 4 cases of interstitial pneumonitis in the one-year Herceptin treatment arm compared to none in the observation arm at a median follow-up duration of 12.6 months.
Metastatic Breast Cancer
Among women receiving Herceptin for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the
post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see Warnings and Precautions (5.4).
Thrombosis/Embolism
In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving Herceptin and chemotherapy compared to chemotherapy alone in three studies (2.6% vs. 1.5% [Study 1], 2.5% and 3.7% vs. 2.2% [Study 4] and 2.1% vs. 0% [Study 5]).
Diarrhea
Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC
Grade 2−5 diarrhea (6.7% vs. 5.4% [Study 1]) and of NCI-CTC Grade 3−5 diarrhea (2.2% vs. 0%
[Study 2]), and of Grade 1−4 diarrhea (7% vs. 1% [Study 3; one-year Herceptin treatment at
12.6 months median duration of follow-up]) were higher in patients receiving Herceptin as compared to controls. In Study 4, the incidence of Grade 3−4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1−4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving Herceptin. Of patients receiving Herceptin as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving Herceptin in combination with chemotherapy for treatment of metastatic breast cancer.
Renal Toxicity
In Study 7 (metastatic gastric cancer) on the Herceptin-containing arm as compared to the chemotherapy alone arm the incidence of renal impairment was 18% compared to 14.5%. Severe (Grade 3/4) renal failure was 2.7% on the Herceptin-containing arm compared to 1.7% on the chemotherapy only arm. Treatment discontinuation for renal insufficiency/failure was 2% on the Herceptin-containing arm and 0.3% on the chemotherapy only arm.
In the post-marketing setting, rare cases of nephrotic syndrome with pathologic evidence of
